This is an application for a one-time renewal of K24 Midcareer Investigator Award in aging and Alzheimer's disease (AD) patient-oriented research. The candidate, Reisa A. Sperling, M.D. M.MSc., is a neurologist with a strong track record as a productive clinical investigator and research mentor. The overarching aims of the candidates' research program are to: 1) elucidate the neural underpinnings of memory decline in aging and early AD; 2) develop sensitive imaging markers to track the progression of early AD; and 3) facilitate earlier intervention with potential disease-modifying treatments in the preclinical stags of AD. The candidate currently leads several ongoing NIH and foundation-funded multimodality imaging projects in aging, preclinical, and prodromal AD, as well as a large secondary prevention trial in preclinical AD. The candidate will continue to use her funded research as a platform for the mentorship of young patient-oriented investigators, and to promote a multidisciplinary approach to the study of cognitive aging and early AD. The candidates' mentees have the opportunity to train in functional, structural, and molecular imaging techniques, cognitive neuroscience, neuropsychological assessment, biostatistics, and clinical trial design as they apply to aging and early AD research, drawing on expertise from an outstanding group of collaborators. Trainees will also be able to participate in research seminars, statistical courses and imaging workshops, career development and grant- writing workshops provided by Harvard Catalyst CTSC, T32 and other training grants, as well as formal didactic course work through the Catalyst, Harvard Medical School, Harvard School of Public Health, and Massachusetts Institute of Technology. A new component proposed for the K24 renewal is mentoring on mentoring to teach developing investigators how to effectively mentor their own mentees as they transition to independence. The candidate has successfully mentored more than 20 fellow and junior faculty trainees over the past 5 years of the initial K24 award, including multiple women and several minority young researchers, who have published over 60 manuscripts and have garnered multiple honors and funding for their work. The K24 renewal research project proposes to investigate the influence of sex (gender) on AD imaging biomarkers and risk of cognitive decline, which will provide many new research opportunities for the candidate's mentees. To further her own continued professional development through the K24 mechanism, the candidate will acquire training in sex-based biology and advanced analytic methodology, and will continue to enhance her mentoring skills through formal mentoring and leadership training. This K24 renewal is critically important for the candidate to continue to grow and foster her clinical research career development and, most essentially, to protect her time to mentor the next generation of investigators committed to early AD patient-oriented research.